JP7103953B2 - Antibody drug conjugate with a derivative of amatoxin as a drug - Google Patents
Antibody drug conjugate with a derivative of amatoxin as a drug Download PDFInfo
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- JP7103953B2 JP7103953B2 JP2018562186A JP2018562186A JP7103953B2 JP 7103953 B2 JP7103953 B2 JP 7103953B2 JP 2018562186 A JP2018562186 A JP 2018562186A JP 2018562186 A JP2018562186 A JP 2018562186A JP 7103953 B2 JP7103953 B2 JP 7103953B2
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- adc
- pharmaceutically acceptable
- acceptable salt
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- 229940049595 antibody-drug conjugate Drugs 0.000 title claims description 62
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Description
関連出願への相互参照
本出願は、2016年5月31日に出願された米国仮特許出願第62/343,825号に対する優先権を主張し、この出願の内容は本明細書において参照として援用される。
Cross-reference to related applications This application claims priority over US Provisional Patent Application No. 62 / 343,825 filed May 31, 2016, the content of which is incorporated herein by reference. ..
技術分野
本開示は、標的化抗体にコンジュゲートしてADC(抗体薬物コンジュゲート)を形成するアマニチンの誘導体を提供する。
Technical Fields The present disclosure provides derivatives of amanitin that conjugate to targeted antibodies to form ADCs (antibody drug conjugates).
背景
アマトキシンは、8個のアミノ酸単位を有する剛性二環式ペプチドである。これらの化合物は、様々なキノコ種(例えば、Amanita phalloides(タマゴテングダケとしても公知)、Galerina marginata、Lepiota brunneo-incamata)から単離されるか、または合成により調製される。様々なキノコ種が、多様な量の様々なアマトキシンファミリーメンバーを含有している。このファミリーの一員であるアルファ-アマニチンは、真核生物RNAポリメラーゼII(EC2.7.7.6)の阻害剤であり、比較的程度は低いがRNAポリメラーゼIIIの阻害剤であり、それによって、転写およびタンパク質生合成を阻害することが公知である。Wieland(1983年)Int. J. Pept. Protein Res.22巻(3号):257~276頁。アルファ-アマニチンは、RNAポリメラーゼIIに非共有結合的に結合し、ゆっくり解離するため、酵素が回復する可能性は低い。転写阻害が長引くと、細胞アポトーシスが誘発されると考えられる。
Background Amatoxin is a rigid bicyclic peptide with 8 amino acid units. These compounds are isolated from various mushroom species (eg, Amanita phalloides (also known as Amanita amanita), Galerina marginata, Lepiota brunneo-incamata) or are prepared synthetically. Different mushroom species contain different amounts of different amatoxin family members. Alpha-amanitin, a member of this family, is an inhibitor of eukaryotic RNA polymerase II (EC 2.7.7.6) and, to a lesser extent, an inhibitor of RNA polymerase III, thereby. It is known to inhibit transcription and protein biosynthesis. Wieland (1983) Int. J. Pept. Protein Res. Vol. 22 (No. 3): pp. 257-276. Alpha-amanitin binds non-covalently to RNA polymerase II and dissociates slowly, so the enzyme is unlikely to recover. Prolonged transcriptional inhibition is thought to induce cell apoptosis.
例示的なアマトキシンとして、
腫瘍細胞を死滅させるか、または阻害する薬物を含めた細胞傷害剤または細胞増殖抑制剤を局所送達するために抗体-薬物コンジュゲート(ADC)を使用することによって、腫瘍への薬物部分の標的化送達およびその細胞内蓄積が可能になる。SyrigosおよびEpenetos(1999年)Anticancer Res.19巻:605~614頁;Niculescu-DuvazおよびSpringer(1997年)Adv. Drug Delivery Rev.26巻:151~172頁;米国特許第4,975,278号;Baldwinら(1986年)Lancet(1986年3月15日):603~05頁;Thorpe(1985年)「Antibody Carriers of Cytotoxic Agents in Cancer Therapy: A Review」、Monoclonal Antibodies '84: Biological and Clinical Applications、A. Pincheraら(編)、475~506頁。このタイプの送達機序は、コンジュゲートしていない薬物薬剤の全身投与から生じるおそれがある正常細胞への毒性を、最小限に抑える一助になる。毒素は、チューブリン結合、DNA結合、またはトポイソメラーゼ阻害を含めた様々な機序を介して、それらの細胞傷害作用および細胞増殖抑制作用を引き起こすことができる。ポリクローナル抗体およびモノクローナル抗体の両方が、これらの戦略において有用であると報告されている。Rowlandら(1986年)Cancer Immunol. Immunother.21巻:183~87頁。抗体-毒素コンジュゲートにおいて使用される毒素には、放射性同位体、細菌性毒素、例えばジフテリア毒素、植物毒素、例えばリシン、真菌毒素、例えばアマトキシン(国際公開第2010/115629号、国際公開第2012/041504号または国際公開第2012/119787号)、ならびに低分子毒素、例えばゲルダナマイシン(Mandlerら(2000年)J. Natl. Cancer Inst.92巻(19号):1573~1581頁;Mandlerら(2000年)Bioorg. Med. Chem. Lett.10巻:1025~1028頁;Mandlerら(2002年)Bioconjugate Chem.13巻:786~791頁)、マイタンシノイド(欧州特許第1391213号;Liuら(1996年)Proc. Natl. Acad. Sci. USA 93巻:8618~8623頁)、カリチアマイシン(Lodeら(1998年)Cancer Res.58巻:2928頁;Hinmanら(1993年)Cancer Res.53巻:3336~3342頁)、ダウノマイシン、ドキソルビシン、メトトレキセート、およびビンデシン(Rowlandら(1986年)、上記)が含まれる。 Targeting drug moieties to tumors by using antibody-drug conjugates (ADCs) to locally deliver cytotoxic or cell proliferation inhibitors, including drugs that kill or inhibit tumor cells. Allows delivery and its intracellular accumulation. Syrigos and Epenetos (1999) Anticancer Res. 19: 605-614; Niculescu-Duvaz and Springer (1997) Adv. Drug Delivery Rev. 26: 151-172; US Pat. No. 4,975,278 Baldwin et al. (1986) Lancet (March 15, 1986): pp. 603-05; Thorpe (1985) "Antibody Carriers of Cytotoxic Agents in Cancer Therapy: A Review", Monoclonal Antibodies '84: Biological and Clinical Applications , A. Pinchera et al. (Edit), pp. 475-506. This type of delivery mechanism helps to minimize the toxicity to normal cells that may result from systemic administration of unconjugated drugs. Toxins can cause their cytotoxic and cell proliferation inhibitory effects through a variety of mechanisms, including tubulin binding, DNA binding, or topoisomerase inhibition. Both polyclonal and monoclonal antibodies have been reported to be useful in these strategies. Rowland et al. (1986) Cancer Immunol. Immunother. Vol. 21, pp. 183-87. Toxins used in antibody-toxin conjugates include radioactive isotopes, bacterial toxins such as diphtheria toxins, plant toxins such as lysine, fungal toxins such as amatoxin (International Publication No. 2010/115629, International Publication No. 2012 / 041504 or WO 2012/119877), as well as low molecular weight toxins such as geldanamycin (Mandler et al. (2000) J. Natl. Cancer Inst. 92 (19): 1573-1581; Mandler et al. (2000). 2000) Bioorg. Med. Chem. Lett. Volume 10: pp. 1025-1028; Mandler et al. (2002) Bioconjugate Chem. Volume 13: pp. 786-791), Maytansinoid (European Patent No. 1391213; Liu et al. 1996) Proc. Natl. Acad. Sci. USA 93: 8618-8623), Calithiamycin (Lode et al. (1998) Cancer Res. 58: 2928; Hinman et al. (1993) Cancer Res. 53) Volumes: 3336-3342), daunomycin, doxorubicin, methotrexate, and bindesin (Rowland et al. (1986), supra).
チオ尿素リンカー-キレーターを介して111Inまたは90Y放射性同位体と接続されたマウスIgGlカッパモノクローナル抗体(正常Bリンパ球および悪性Bリンパ球の表面上に見出されるCD20抗原を対象とする)から構成された抗体-放射性同位体コンジュゲートである、ZEVALIN(登録商標)(イブリツモマブチウキセタン、Biogen/Idec)を含めたいくつかの抗体-薬物コンジュゲートは、臨床治験において、がんに対して有望な結果をもたらすことが示されている。 Consists of mouse IgGl kappa monoclonal antibody (targeting CD20 antigens found on the surface of normal and malignant B lymphocytes) linked to 111In or 90Y radioisotopes via a thiourea linker-killer. Several antibody-drug conjugates, including the antibody-radioisotope conjugate ZEVALIN® (Ibritumomab tiuxetan, Biogen / Idec), are promising for cancer in clinical trials. It has been shown to produce results.
腫瘍細胞を死滅させるか、または阻害する薬物を含めた細胞傷害剤または細胞増殖抑制剤を局所送達するために抗体-薬物コンジュゲート(ADC)を使用することによって、腫瘍への薬物部分の標的化送達およびその細胞内蓄積が可能になる。このタイプの送達機序は、コンジュゲートしていない薬物薬剤の全身投与から生じるおそれがある正常細胞への毒性を、最小限に抑える一助になる。毒素は、チューブリン結合を含めた様々な機序を介して、それらの細胞傷害作用および細胞増殖抑制作用を引き起こすことができる。 Targeting drug moieties to tumors by using antibody-drug conjugates (ADCs) to locally deliver cytotoxic or cell proliferation inhibitors, including drugs that kill or inhibit tumor cells. Allows delivery and its intracellular accumulation. This type of delivery mechanism helps to minimize the toxicity to normal cells that may result from systemic administration of unconjugated drugs. Toxins can cause their cytotoxic and cell proliferation inhibitory effects through a variety of mechanisms, including tubulin binding.
したがって、望ましい薬学的特性を有する強力なRNAポリメラーゼ阻害剤である抗体コンジュゲートが、依然必要である。 Therefore, antibody conjugates, which are potent RNA polymerase inhibitors with desirable pharmaceutical properties, are still needed.
要旨
本開示は、ADC(抗体薬物コンジュゲート)構造で使用される、改善されたアマトキシン誘導体を提供する。より具体的には、本開示は、式Iの構造を有する抗体薬物コンジュゲート(ADC)
[式中、
Abは、モノクローナル抗体であり、
L1-L2は、
L2-Xは、
波線は、Dとの結合点を示し、
Dは、アマトキシンから誘導された薬物部分の活性薬剤であり、以下の構造を有するアルファ-アマニチン、ベータ-アマニチン、ガンマ-アマニチン、およびイプシロン-アマニチンからなる群から選択され、
L2は、アミノ酸、10個までのアミノ酸からなるペプチド、-(CH2)p-、-(CH2CH2O)m-、-C(O)NH-、-NHC(O)-、PAB(p-アミノベンジル)、Val-Cit-PAB、Val-Ala-PAB、Ala-Ala-Asn-PAB、-R6OC(O)NR5-、-R8-S-S-R7、およびそれらの組合せからなる群から選択されるリンカーであり、
R5は、水素、C1~6アルキル、-(CH2)p-、-(CH2CH2O)m-、およびそれらの組合せからなる群から選択され、
R6は、アミノ酸、10個までのアミノ酸からなるペプチド、C1~6アルキル、-(CH2)p-、-(CH2CH2O)m-、-C(O)NH-、-NHC(O)-、PAB、Val-Cit-PAB、Val-Ala-PAB、Ala-Ala-Asn-PAB、およびそれらの組合せからなる群から選択され、
R7は、C2~6アルキレン、または-(CH2CH2O)m-であり、
R8は、アミノ酸、10個までのアミノ酸からなるペプチド、C1~6アルキル、C1~6アルキレン、置換C1~6アルキレン、-C(O)NH-、-C(O)-NH-CHR9-CR10R11-、-NHC(O)-CHR9-CR10R11-、-(CH2CH2O)m-、PAB、Val-Cit-PAB、Val-Ala-PAB、Ala-Ala-Asn-PAB、およびそれらの組合せからなる群から選択され、
R9は、水素、C1~6アルキル、C1~6アルキレン、-(CH2CH2O)m-、-C(O)NH-、-NHC(O)-、-C(O)NH-(CH2)p-SO3H、C(O)NH-(CH2)p-CO2H、-NHC(O)-(CH2)p-SO3H、-NHC(O)-(CH2)p-CO2Hおよびそれらの組合せからなる群から選択され、
R10およびR11は、それぞれ独立に、水素、C1~6アルキル、およびそれらの組合せからなる群から選択され、
-R6OC(O)NR5-は、R5またはR6を介してL1と接続し、
-R8-S-S-R7-は、R8を介してL1と接続し、
mは、1~24の整数であり、
pは、1~6の整数である]。
Abstract The present disclosure provides improved amatoxin derivatives for use in ADC (antibody drug conjugate) structures. More specifically, the present disclosure is an antibody drug conjugate (ADC) having the structure of formula I.
Ab is a monoclonal antibody,
L 1 -L 2 is
L2 - X is
The wavy line indicates the point of connection with D,
D is the active agent of the drug moiety derived from amatoxin and is selected from the group consisting of alpha-amanitin, beta-amanitin, gamma-amanitin, and epsilon-amanitin having the following structures:
L 2 is an amino acid, a peptide consisting of up to 10 amino acids,-(CH 2 ) p -,-(CH 2 CH 2 O) m- , -C (O) NH-, -NHC (O)-, PAB. (P-Aminobenzyl), Val-Cit-PAB, Val-Ala-PAB, Ala-Ala-Asn-PAB, -R 6 OC (O) NR 5- , -R 8 -S-S-R 7 , and A linker selected from the group consisting of combinations thereof.
R 5 is selected from the group consisting of hydrogen, C 1-6 alkyl,-(CH 2 ) p -,-(CH 2 CH 2 O) m- , and combinations thereof.
R 6 is an amino acid, a peptide consisting of up to 10 amino acids, C 1 to 6 alkyl,-(CH 2 ) p -,-(CH 2 CH 2 O) m- , -C (O) NH-, -NHC. (O)-, PAB, Val-Cit-PAB, Val-Ala-PAB, Ala-Ala-Asn-PAB, and combinations thereof are selected from the group.
R 7 is C 2 to 6 alkylene, or − (CH 2 CH 2 O) m −.
R 8 is an amino acid, a peptide consisting of up to 10 amino acids, C 1-6 alkyl, C 1-6 alkylene, substituted C 1-6 alkylene, -C (O) NH-, -C (O) -NH- CHR 9 -CR 10 R 11- , -NHC (O) -CHR 9 -CR 10 R 11 -,-(CH 2 CH 2 O) m- , PAB, Val-Cit-PAB, Val-Ala-PAB, Ala -Selected from the group consisting of Ala-Asn-PAB and combinations thereof,
R 9 is hydrogen, C 1 to 6 alkyl, C 1 to 6 alkylene,-(CH 2 CH 2 O) m- , -C (O) NH-, -NHC (O)-, -C (O) NH. -(CH 2 ) p-SO 3 H, C (O) NH- (CH 2 ) p-CO 2 H, -NHC (O)-(CH 2 ) p-SO 3 H, -NHC (O)-( CH 2 ) Selected from the group consisting of p-CO 2 H and combinations thereof,
R 10 and R 11 are independently selected from the group consisting of hydrogen, C1-6 alkyl, and combinations thereof.
-R 6 OC (O) NR 5 -is connected to L 1 via R 5 or R 6 and
-R 8 -SS-R 7- is connected to L 1 via R 8 and
m is an integer from 1 to 24,
p is an integer from 1 to 6].
別の態様では、式Iの構造を有する化合物のL2は、アミノ酸、10個までのアミノ酸からなるペプチド、-(CH2)p-、-(CH2CH2O)m-、-C(O)NH-、-NHC(O)-、PAB(p-アミノベンジル)、-Val-Cit-PAB-、-Val-Ala-PAB-、-Ala-Ala-Asn-PAB-、-R6OC(O)NR5-、-R8-S-S-R7、およびそれらの組合せからなる群から選択されるリンカーであり、
R5は、水素、C1~6アルキル、-(CH2)p-、-(CH2CH2O)m-、およびそれらの組合せからなる群から選択され、
R6は、アミノ酸、10個までのアミノ酸からなるペプチド、C1~6アルキル、-(CH2)p-、-(CH2CH2O)m-、-C(O)NH-、-NHC(O)-、PAB、-Val-Cit-PAB-、-Val-Ala-PAB-、-Ala-Ala-Asn-PAB-、およびそれらの組合せからなる群から選択され、
R7は、C2~6アルキレン、または-(CH2CH2O)m-であり、
R8は、アミノ酸、10個までのアミノ酸からなるペプチド、C1~6アルキル、C1~6アルキレン、置換C1~6アルキレン、-C(O)NH-、-C(O)-NH-CHR9-CR10R11-、-NHC(O)-CHR9-CR10R11-、-(CH2CH2O)m-、PAB、-Val-Cit-PAB-、-Val-Ala-PAB-、-Ala-Ala-Asn-PAB-、およびそれらの組合せからなる群から選択され、
R9は、水素、C1~6アルキル、C1~6アルキレン、-(CH2CH2O)m-、-C(O)NH-、-NHC(O)-、-C(O)NH-(CH2)p-SO3H、C(O)NH-(CH2)p-CO2H、-NHC(O)-(CH2)p-SO3H、-NHC(O)-(CH2)p-CO2Hおよびそれらの組合せからなる群から選択され、
R10およびR11は、それぞれ独立に、水素、C1~6アルキル、およびそれらの組合せからなる群から選択され、
-R6OC(O)NR5-は、R5またはR6を介してL1と接続し、
-R8-S-S-R7-は、R8を介してL1と接続し、
mは、1~24の整数であり、
pは、1~6の整数であり、残りの値は、式Iについて前述される通りである。
In another aspect, L 2 of the compound having the structure of formula I is an amino acid, a peptide consisting of up to 10 amino acids,-(CH 2 ) p -,-(CH 2 CH 2 O) m- , -C ( O) NH-, -NHC (O)-, PAB (p-aminobenzyl), -Val-Cit-PAB-, -Val-Ala-PAB-, -Ala-Ala-Asn-PAB-, -R 6 OC (O) A linker selected from the group consisting of NR 5- , -R 8 -S-SR 7 , and combinations thereof.
R 5 is selected from the group consisting of hydrogen, C 1-6 alkyl,-(CH 2 ) p -,-(CH 2 CH 2 O) m- , and combinations thereof.
R 6 is an amino acid, a peptide consisting of up to 10 amino acids, C 1 to 6 alkyl,-(CH 2 ) p -,-(CH 2 CH 2 O) m- , -C (O) NH-, -NHC. (O)-, PAB, -Val-Cit-PAB-, -Val-Ala-PAB-, -Ala-Ala-Asn-PAB-, and combinations thereof are selected from the group.
R 7 is C 2 to 6 alkylene, or − (CH 2 CH 2 O) m −.
R 8 is an amino acid, a peptide consisting of up to 10 amino acids, C 1 to 6 alkyl, C 1 to 6 alkylene, substituted C 1 to 6 alkylene, -C (O) NH-, -C (O) -NH- CHR 9 -CR 10 R 11-, -NHC (O) -CHR 9-CR 10 R 11 - , - (CH 2 CH 2 O) m- , PAB, -Val-Cit-PAB-, -Val-Ala- Selected from the group consisting of PAB-, -Ala-Ala-Asn-PAB-, and combinations thereof.
R 9 is hydrogen, C 1 to 6 alkyl, C 1 to 6 alkylene,-(CH 2 CH 2 O) m- , -C (O) NH-, -NHC (O)-, -C (O) NH. -(CH 2 ) p-SO 3 H, C (O) NH- (CH 2 ) p-CO 2 H, -NHC (O)-(CH 2 ) p-SO 3 H, -NHC (O)-( CH 2 ) Selected from the group consisting of p-CO 2 H and combinations thereof,
R 10 and R 11 are independently selected from the group consisting of hydrogen, C1-6 alkyl, and combinations thereof.
-R 6 OC (O) NR 5 -is connected to L 1 via R 5 or R 6 and
-R 8 -SS-R 7- is connected to L 1 via R 8 and
m is an integer from 1 to 24,
p is an integer from 1 to 6, and the remaining values are as described above for Equation I.
さらに別の態様では、式Iの構造を有する化合物のL2は、アミノ酸、10個までのアミノ酸からなるペプチド、-(CH2)p-、-(CH2CH2O)m-、-C(O)NH-、-NH(4-フェニル)CH2O-、-Val-Cit-NH(4-フェニル)CH2O-、-Val-Ala-NH(4-フェニル)CH2O-、-Ala-Ala-Asn-NH(4-フェニル)CH2O-、-R6OC(O)NR5-、-R8-S-S-R7-、およびそれらの組合せからなる群から選択されるリンカーであり、
R5は、水素、C1~6アルキル、-(CH2)p-、-(CH2CH2O)m-、およびそれらの組合せからなる群から選択され、
R6は、アミノ酸、10個までのアミノ酸からなるペプチド、C1~6アルキル、-(CH2)p-、-(CH2CH2O)m-、-C(O)NH-、-NH(4-フェニル)CH2-、-Val-Cit-NH(4-フェニル)CH2-、-Val-Ala-NH(4-フェニル)CH2-、-Ala-Ala-Asn-NH(4-フェニル)CH2-、およびそれらの組合せからなる群から選択され、
R7は、C2~6アルキレン、または-(CH2CH2O)m-であり、
R8は、アミノ酸、10個までのアミノ酸からなるペプチド、C1~6アルキル、C1~6アルキレン、置換C1~6アルキレン、-C(O)-NH-CHR9-CR10R11-、-NHC(O)-CHR9-CR10R11-、-(CH2CH2O)m-、-PAB-、-Val-Cit-NH(4-フェニル)CH2-、-Val-Ala-NH(4-フェニル)CH2-、-Ala-Ala-Asn-NH(4-フェニル)CH2-、およびそれらの組合せからなる群から選択され、
R9は、水素、C1~6アルキル、C1~6アルキレン、-(CH2CH2O)m-、-C(O)NH-、-NHC(O)-、-C(O)NH-(CH2)p-SO3H、-C(O)NH-(CH2)p-CO2H、-NHC(O)-(CH2)p-SO3H、-NHC(O)-(CH2)p-CO2Hおよびそれらの組合せからなる群から選択され、
R10およびR11は、それぞれ独立に、水素、C1~6アルキル、およびそれらの組合せからなる群から選択され、
-R6OC(O)NR5-は、R6を介してL1と接続し、
-R8-S-S-R7-は、R8を介してL1と接続し、
mは、1~24の整数であり、
pは、1~6の整数であり、残りの値は、式Iについて前述される通りである。
In yet another embodiment, L 2 of the compound having the structure of formula I is an amino acid, a peptide consisting of up to 10 amino acids,-(CH 2 ) p -,-(CH 2 CH 2 O) m- , -C. (O) NH-, -NH (4-phenyl) CH 2 O-, -Val-Cit-NH (4-phenyl) CH 2 O-, -Val-Ala-NH (4-phenyl) CH 2 O-, -Ala-Ala-Asn-NH (4-phenyl) CH 2 O-, -R 6 OC (O) NR 5- , -R 8 -S-S-R 7- , and a combination thereof. Is a linker that is
R 5 is selected from the group consisting of hydrogen, C 1-6 alkyl,-(CH 2 ) p -,-(CH 2 CH 2 O) m- , and combinations thereof.
R 6 is an amino acid, a peptide consisting of up to 10 amino acids, C 1 to 6 alkyl,-(CH 2 ) p -,-(CH 2 CH 2 O) m- , -C (O) NH-, -NH. (4-Phenyl) CH 2- , -Val-Cit-NH (4-Phenyl) CH 2- , -Val-Ala-NH (4-Phenyl) CH 2- , -Ala-Ala-Asn-NH (4-Fin) Selected from the group consisting of phenyl) CH 2- , and combinations thereof,
R 7 is C 2 to 6 alkylene, or − (CH 2 CH 2 O) m −.
R 8 is an amino acid, a peptide consisting of up to 10 amino acids, C 1 to 6 alkyl, C 1 to 6 alkylene, substituted C 1 to 6 alkylene, -C (O) -NH-CHR 9 -CR 10 R 11- , -NHC (O) -CHR 9 -CR 10 R 11 -,-(CH 2 CH 2 O) m- , -PAB-, -Val-Cit-NH (4-phenyl) CH 2- , -Val-Ala Selected from the group consisting of -NH (4-phenyl) CH 2- , -Ala-Ala-Asn-NH (4-phenyl) CH 2- , and combinations thereof.
R 9 is hydrogen, C 1 to 6 alkyl, C 1 to 6 alkylene,-(CH 2 CH 2 O) m- , -C (O) NH-, -NHC (O)-, -C (O) NH. -(CH 2 ) p-SO 3 H, -C (O) NH- (CH 2 ) p-CO 2 H, -NHC (O)-(CH 2 ) p-SO 3 H, -NHC (O)- Selected from the group consisting of (CH 2 ) p-CO 2 H and combinations thereof,
R 10 and R 11 are independently selected from the group consisting of hydrogen, C1-6 alkyl, and combinations thereof.
-R 6 OC (O) NR 5 --is connected to L 1 via R 6 and
-R 8 -SS-R 7- is connected to L 1 via R 8 and
m is an integer from 1 to 24,
p is an integer from 1 to 6, and the remaining values are as described above for Equation I.
好ましくは、Dは、式IIの構造
R1は、NH2またはOR2であり、R2は、H、またはC1~C10アルキルであり、R3は、HまたはOHである。
Preferably, D is the structure of formula II.
R 1 is NH 2 or OR 2 , R 2 is H or C 1 to C 10 alkyl, and R 3 is H or OH.
好ましくは、開示されるADCは、
詳細な説明
定義
本明細書で使用される場合、一般的な有機に関する略語は、以下の通り定義される。
Ac アセチル
aq. 水性
BOCまたはBoc tert-ブトキシカルボニル
Bu n-ブチル
℃ 摂氏温度
Cit シトルリン
DCM 塩化メチレン
DEPC ジエチルシアノホスホネート
DIC ジイソプロピルカルボジイミド
DIEA ジイソプロピルエチルアミン
DMA N,N’-ジメチルアセトアミド
DMF N,N’-ジメチルホルムアミド
DMSO ジメチルスルホキシド
EDC 1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド
Et エチル
EtOAc 酢酸エチル
Eq 当量
Fmoc 9-フルオレニルメトキシカルボニル
g グラム
h 時間
HATU 2-(1H-7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウムヘキサフルオロホスフェート
HOBT N-ヒドロキシベンゾトリアゾール
HOSu N-ヒドロキシスクシンイミド
HPLC 高速液体クロマトグラフィー
LC/MS 液体クロマトグラフィー-質量分析
Me メチル
MeOH メタノール
MeCN アセトニトリル
mL ミリリットル
MS 質量分析
PAB p-アミノベンジル
RP-HPLC 逆相HPLC
rt 室温
t-Bu tert-ブチル
TEA トリエチルアミン
Tert、t 第三級
TFA トリフルオロ酢酸(Trifluoracetic acid)
THF テトラヒドロフラン
TLC 薄層クロマトグラフィー
μL マイクロリットル
Definitions As used herein, common organic abbreviations are defined as follows.
Ac Acetyl aq. Aqueous BOC or Boc tert-Butoxycarbonyl Bun-Butyl ° C. Cit Citrulin DCM Methyl Chloride DEPC Diisopropyl Carbodiimide DIEA Diisopropyl Ethylamine DMA N, N'-Dimethylacetonitrile DMF N, N'-Dimethylformamide DMSO Dimethylsulfoxide EDC 1-Ethyl-3- (3-Didimethylaminopropyl) Carbodiimide Et Ethyl EtOAc Ethyl Acetate Eq Equivalent Fmoc 9-Fluorenylmethoxycarbonyl g gram h Hours HATU 2- (1H-7-azabenzotriazole-1-yl)- 1,1,3,3-Tetramethyluronium Hexafluorophosphate HOBT N-Hydroxybenzotriazol HOSu N-Hydroxysuccinimide HPLC High Performance Liquid Chromatography LC / MS Liquid Chromatography-Mass Analysis Me Methyl MeOH Methanol MeCN Acetonitrile mL Milliliter MS Mass Analysis PAB p-aminobenzyl RP-HPLC Reverse phase HPLC
rt Room temperature t-Bu tert-Butyl TEA Triethylamine Tert, t Tertiary TFA Trifluoracetic acid
THF Tetrahydrofuran TLC Thin Layer Chromatography μL Microliter
ハイフン(-)は、使用される場合、基が、定義された変数に結合している点を示す。左側にあるハイフンは、式(I)の左側の構造的構成成分との接続を示し、右側にあるハイフンは、式(I)の右側の構造的構成成分との接続を示す。例えば、他に特定されない限り、L2が-(CH2CH2O)m-と定義される場合、これは、L1との結合が、-CH2の炭素にあり、Xとの結合が酸素原子にあることを意味する。 A hyphen (-), when used, indicates that the group is attached to a defined variable. The hyphen on the left side indicates the connection with the structural component on the left side of the formula (I), and the hyphen on the right side indicates the connection with the structural component on the right side of the formula (I). For example, unless otherwise specified, if L 2 is defined as-(CH 2 CH 2 O) m- , this means that the bond with L 1 is on the carbon of -CH 2 and the bond with X is. It means that it is in the oxygen atom.
一般合成手順。-酸からの活性化エステル(例えばNHS)の形成
酸を、DCM(塩化メチレン)に溶解させ、必要に応じてDMF(N,N’ジメチルホルムアミド)を添加して溶解を助けた。N-ヒドロキシスクシンイミド(1.5当量)を添加した後、EDC.HCl(1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド)(1.5当量)を添加した。酸の大部分が消費されるまで、反応混合物を室温で1時間撹拌した。反応の進行を、RP-HPLCによってモニタリングした。次に、混合物をDCMで希釈し、クエン酸(10%水溶液)およびブラインで逐次的に洗浄した。有機層を乾燥させ、濃縮乾固させた。粗製生成物を、RP-HPLCまたはシリカゲルカラムクロマトグラフィーによって任意選択で精製した。
General synthesis procedure. -Formation of activated ester (eg NHS) from acid The acid was dissolved in DCM (methylene chloride) and DMF (N, N'dimethylformamide) was added as needed to aid in the dissolution. After adding N-hydroxysuccinimide (1.5 eq), EDC. HCl (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide) (1.5 eq) was added. The reaction mixture was stirred at room temperature for 1 hour until most of the acid was consumed. The progress of the reaction was monitored by RP-HPLC. The mixture was then diluted with DCM and washed sequentially with citric acid (10% aqueous solution) and brine. The organic layer was dried and concentrated to dryness. The crude product was optionally purified by RP-HPLC or silica gel column chromatography.
実施例1
化合物6の調製
Preparation of
アルファ-アマニチン(amainitin)1(46mg、50μmol)の無水ジメチルスルホキシド(DMSO)(1mL)溶液に、ビス(4-ニトロフェノール)カーボネート(17mg、55μmol)を添加した後、ジイソプロピルエチルアミン(DIEA、10μL)を添加した。混合物を室温で30分間撹拌した。化合物3(12mg)を添加した後、DIEA(10μL)を添加した。LC/MSによって、すべての化合物2が1時間後に消費されたことが示された。すべての溶媒を減圧下で除去し、残留物をジクロロメタン(DCM)(20%、v/v、2mL)中トリフルオロ酢酸(TFA)で処理した。30分後に反応混合物を濃縮し、残留物を逆相HPLCによって精製して、凍結乾燥後に、化合物4を白色の固体としてTFA塩形態で得た(45mg、78%)。MS:m/z1033.4(M+H+)。
To a solution of alpha-amainitin 1 (46 mg, 50 μmol) in anhydrous dimethyl sulfoxide (DMSO) (1 mL) is added bis (4-nitrophenol) carbonate (17 mg, 55 μmol), followed by diisopropylethylamine (DIEA, 10 μL). Was added. The mixture was stirred at room temperature for 30 minutes. After adding compound 3 (12 mg), DIEA (10 μL) was added. LC / MS showed that all compound 2 was consumed after 1 hour. All solvents were removed under reduced pressure and the residue was treated with trifluoroacetic acid (TFA) in dichloromethane (DCM) (20%, v / v, 2 mL). After 30 minutes, the reaction mixture was concentrated and the residue was purified by reverse phase HPLC and lyophilized to give
化合物4(45mg)を、無水ジメチルホルムアミド(DMF、1mL)に溶解させ、9-フルオレニルメチルオキシカルボニル-バリル-シトルリル-(4-アミノベンジル)-(4-ニトロフェニル)カーボネート(Fmoc-Val-Cit-PAB-PNP、38mg)を添加した後、DIEA(20μL)を添加した。混合物を室温で2時間撹拌した。LC/MS分析によって反応の完了が示された。ピペリジン(50μL)を添加し、2時間後、酢酸(200μL)を添加することによって反応混合物を中和した。粗製混合物を、逆相HPLCによって直接精製して、凍結乾燥後に、化合物5を白色の固体としてTFA塩形態で得た(48mg、80%)。MS:m/z1438.7(M+H+)。
Compound 4 (45 mg) is dissolved in anhydrous dimethylformamide (DMF, 1 mL) and 9-fluorenylmethyloxycarbonyl-valyl-citrryl- (4-aminobenzyl)-(4-nitrophenyl) carbonate (Fmoc-Val). -Cit-PAB-PNP, 38 mg) was added, followed by DIEA (20 μL). The mixture was stirred at room temperature for 2 hours. LC / MS analysis showed the reaction was complete. Piperidine (50 μL) was added and after 2 hours, the reaction mixture was neutralized by adding acetic acid (200 μL). The crude mixture was directly purified by reverse phase HPLC and lyophilized to give
撹拌した化合物5(16mg、10μmol)のDMF(1mL)溶液に、N-ε-マレイミドカプロイルオキシスクシンイミドエステル(4mg)を添加した後、DIEA(4μL)を添加した。混合物を室温で2時間撹拌した。粗製反応混合物を、精製のために分取HPLCカラムに注入した。化合物6を、凍結乾燥後に白色の固体として得た(12mg)。MS:m/z1631.8(M+H+)。
N-ε-maleimide caproyloxysuccinimide ester (4 mg) was added to a stirred solution of compound 5 (16 mg, 10 μmol) in DMF (1 mL), and then DIEA (4 μL) was added. The mixture was stirred at room temperature for 2 hours. The crude reaction mixture was injected into a preparative HPLC column for purification.
実施例2
化合物8の調製
Preparation of
撹拌した化合物5(16mg、10μmol)のDMF(1mL)溶液に、酸7(6mg)を添加した後、ジイソプロピルカルボジイミド(5μL)を添加した。混合物を室温で2時間撹拌した。粗製反応混合物を、精製のために分取HPLCカラムに注入した。化合物8を、凍結乾燥後に白色の固体として得た(8mg)。MS:m/z1761.8(M+H+)。
Acid 7 (6 mg) was added to a stirred solution of compound 5 (16 mg, 10 μmol) in DMF (1 mL), and then diisopropylcarbodiimide (5 μL) was added. The mixture was stirred at room temperature for 2 hours. The crude reaction mixture was injected into a preparative HPLC column for purification.
実施例3
化合物10の調製
Preparation of
撹拌した化合物2(30μmol)のDMSO(1mL)溶液に、アミン9(40mg)を添加した後、DIEA(15μL)を添加した。混合物を室温で16時間撹拌した。粗製反応混合物を、精製のために分取HPLCカラムに注入した。化合物10を、凍結乾燥後に白色の固体として得た(32mg)。MS:m/z2046.2(M+H+)。
Amine 9 (40 mg) was added to a stirred solution of compound 2 (30 μmol) in DMSO (1 mL), followed by DIEA (15 μL). The mixture was stirred at room temperature for 16 hours. The crude reaction mixture was injected into a preparative HPLC column for purification.
化合物10を、一般手順に従って対応する活性化エステルに変換した後、抗体にコンジュゲートさせた。
実施例4
化合物14の調製
Preparation of
撹拌した化合物2(50μmol)のDMSO(1mL)溶液に、DMF(1mL)中アミン11(65mg)を添加した後、DIEA(20μL)を添加した。混合物を室温で16時間撹拌した。ピペリジン(100μL)を添加した。30分後、混合物を逆相HPLCによって直接精製して、化合物12を白色の固体としてTFA塩形態で得た(54mg)。MS:m/z1862.1(M+H+)。
Amine 11 (65 mg) in DMF (1 mL) was added to a stirred DMSO (1 mL) solution of compound 2 (50 μmol), followed by DIEA (20 μL). The mixture was stirred at room temperature for 16 hours. Piperidine (100 μL) was added. After 30 minutes, the mixture was directly purified by reverse phase HPLC to give
化合物12(20mg)をDMF(1mL)に溶解させた。無水物13(11mg)を添加した後、DIEA(5μL)を添加した。反応混合物を室温で5分間撹拌し、逆相HPLCによって精製して、凍結乾燥後に、化合物14を白色の固体として得た(19mg)。MS:m/z2203.9(M+H+)。
Compound 12 (20 mg) was dissolved in DMF (1 mL). After adding anhydride 13 (11 mg), DIEA (5 μL) was added. The reaction mixture was stirred at room temperature for 5 minutes, purified by reverse phase HPLC and lyophilized to give
実施例5
化合物17の調製
Preparation of compound 17
撹拌した化合物2(50μmol)のDMSO(1mL)溶液に、DMF(1mL)中アミン15(65mg)を添加した後、DIEA(20μL)を添加した。混合物を室温で16時間撹拌した。ピペリジン(100μL)を添加した。30分後、混合物を逆相HPLCによって直接精製して、化合物16を白色の固体としてTFA塩形態で得た(49mg)。MS:m/z1862.3(M+H+)。
To a stirred solution of compound 2 (50 μmol) in DMSO (1 mL) was added amine 15 (65 mg) in DMF (1 mL), followed by DIEA (20 μL). The mixture was stirred at room temperature for 16 hours. Piperidine (100 μL) was added. After 30 minutes, the mixture was directly purified by reverse phase HPLC to give
化合物16(20mg)をDMF(1mL)に溶解させた。無水物13(11mg)を添加した後、DIEA(5μL)を添加した。反応混合物を室温で5分間撹拌し、逆相HPLCによって精製して、凍結乾燥後に、化合物17を白色の固体として得た(20mg)。MS:m/z2204.1(M+H+)。 Compound 16 (20 mg) was dissolved in DMF (1 mL). After adding anhydride 13 (11 mg), DIEA (5 μL) was added. The reaction mixture was stirred at room temperature for 5 minutes, purified by reverse phase HPLC and lyophilized to give compound 17 as a white solid (20 mg). MS: m / z 2204.1 (M + H + ).
実施例6
化合物21の調製
Preparation of
撹拌した化合物2(50μmol)のDMSO(1mL)溶液に、DMF(1mL)中アミン15(25mg)を添加した後、DIEA(20μL)を添加した。混合物を室温で5時間撹拌した。溶媒を減圧下で除去し、残留物を20%TFA/DCM(2mL)に溶解させた。30分後、混合物を逆相HPLCによって直接精製して、化合物19を白色の固体として得た(31mg)。MS:m/z1309.5(M+NH4 +)。 To a stirred solution of compound 2 (50 μmol) in DMSO (1 mL) was added amine 15 (25 mg) in DMF (1 mL), followed by DIEA (20 μL). The mixture was stirred at room temperature for 5 hours. The solvent was removed under reduced pressure and the residue was dissolved in 20% TFA / DCM (2 mL). After 30 minutes, the mixture was directly purified by reverse phase HPLC to give compound 19 as a white solid (31 mg). MS: m / z 1309.5 (M + NH 4 + ).
撹拌した化合物19(25mg、20μmol)のDMF(1mL)溶液に、酸20(16mg)を添加した後、ジイソプロピルカルボジイミド(8μL)を添加した。混合物を室温で2時間撹拌した。粗製反応混合物を、精製のために分取HPLCカラムに注入した。化合物21を、凍結乾燥後に白色の固体として得た(12mg)。MS:m/z1791.4(M+H+)。
Acid 20 (16 mg) was added to a stirred solution of compound 19 (25 mg, 20 μmol) in DMF (1 mL), followed by diisopropylcarbodiimide (8 μL). The mixture was stirred at room temperature for 2 hours. The crude reaction mixture was injected into a preparative HPLC column for purification.
実施例7
化合物28の調製
Preparation of
撹拌した化合物2(50μmol)のDMSO(1mL)溶液に、DMF(1mL)中アミン30(46mg、50μmol)を添加した後、DIEA(20μL)を添加した。混合物を室温で16時間撹拌した。ピペリジン(100μL)を添加した。30分後、混合物を逆相HPLCによって直接精製して、化合物31を白色の固体としてTFA塩形態で得た(25mg)。MS:m/z1640.5(M+H+)。 Amine 30 (46 mg, 50 μmol) in DMF (1 mL) was added to a stirred solution of compound 2 (50 μmol) in DMSO (1 mL), and then DIEA (20 μL) was added. The mixture was stirred at room temperature for 16 hours. Piperidine (100 μL) was added. After 30 minutes, the mixture was directly purified by reverse phase HPLC to give compound 31 as a white solid in TFA salt form (25 mg). MS: m / z 1640.5 (M + H + ).
化合物31(20mg、11.4μmol)をDMF(1mL)に溶解させた。無水物13(8mg)を添加した後、DIEA(5μL)を添加した。反応混合物を室温で5分間撹拌し、逆相HPLCによって精製して、凍結乾燥後に、化合物28を白色の固体として得た(16mg)。MS:m/z1981.9(M+H+)。
Compound 31 (20 mg, 11.4 μmol) was dissolved in DMF (1 mL). After adding anhydride 13 (8 mg), DIEA (5 μL) was added. The reaction mixture was stirred at room temperature for 5 minutes, purified by reverse phase HPLC and lyophilized to give
実施例8
この実施例は、以下「A」および「B」と示される2つの異なるアマニチン(amatinin)コンジュゲートを比較する比較研究を提供する。
This example provides a comparative study comparing two different amatinin conjugates, hereinafter referred to as "A" and "B".
様々なin vitro細胞死滅アッセイにおいて比較研究を行って、アルファ-アマニチン(amaintin)が、切断可能なカルバメート結合を介してリンカーに結合しているアマニチン抗体コンジュゲート構造A(本開示に報告されている)、およびアルファアマニチンが、切断不可能なエーテル結合を介して結合しているアマニチン抗体コンジュゲート構造B(国際公開第2012/041504号に報告されている)の有効性を評価した(図1の4つのパネルは4種の異なる細胞系に関する)。ADC Aは、試験したすべての4種のHer-2陽性細胞系においてADC Bを完全に上回っていた。 Comparative studies in various in vitro cell killing assays have shown that alpha-amaintin is an amanitin antibody conjugate structure A that binds to a linker via a cleavable carbamate bond (reported herein). ), And the efficacy of the amanitin antibody conjugate structure B (reported in WO 2012/041504), in which alpha amanitin is bound via a non-cleavable assay bond (FIG. 1). The four panels relate to four different cell lines). ADC A completely outperformed ADC B in all four Her-2 positive cell lines tested.
実施例9
この実施例は、特定の細胞においてin vitroで測定された、指定された薬物とコンジュゲートした抗体のEC50アッセイの結果(nM)を提供する。使用した抗体は、抗HER2 IgGクラスの抗体であった。以下の表においてプラスまたはマイナスの印で示される通り、様々なHer2発現レベルの7種の乳がん細胞系を、96ウェルプレートに蒔いた。ADCを連続希釈し、処理のために細胞上に添加し5日間置いた。研究の最後に、細胞増殖をPromega製CellTitreGloによって測定した。EC50(nM)を、50%細胞成長阻害濃度として決定した。成果を挙げる化合物の選択基準には、標的受容体の高い発現を伴って3nM未満のEC50で細胞系を死滅させるなどの高い有効性が含まれていた。また、成果を挙げる候補は、標的受容体の低度の発現と共に対照細胞系(MDA468)の相対的に低度の死滅によって決定される通り、低毒性および良好な治療ウィンドウを有するはずである。ADC22(図3)および24(図2)の両方を、高い有効性および良好な治療ウィンドウを伴う成果を挙げる候補として選択した。
Example 9
This example provides EC50 assay results (nM) of antibodies conjugated to a specified drug, measured in vitro in specific cells. The antibody used was an anti-HER2 IgG class antibody. Seven breast cancer cell lines with various Her2 expression levels were sown on 96-well plates, as indicated by the plus or minus marks in the table below. The ADC was serially diluted, added onto cells for treatment and left for 5 days. At the end of the study, cell proliferation was measured by Promega CellTitreGlo. EC50 (nM) was determined as a 50% cell growth inhibitory concentration. Successful compound selection criteria included high efficacy, such as killing cell lines with EC50s below 3 nM with high expression of target receptors. Also, successful candidates should have low toxicity and a good treatment window, as determined by the relatively low death of the control cell line (MDA468) along with the low expression of the target receptor. Both ADCs 22 (3) and 24 (2) were selected as successful candidates with high efficacy and good treatment window.
実施例10
この実施例は、特定の細胞においてin vitroで測定された、本明細書に記載の指定されたADCのEC50アッセイの結果(nM)を提供する。使用した抗体は、細胞表面上の受容体チロシンキナーゼを標的とする。以下の表においてプラスまたはマイナスの印で示される通り、様々なレベルの受容体発現を伴う8種のがん細胞系を、96ウェルプレートに蒔いた。ADCを連続希釈し、処理のために細胞上に添加し5日間置いた。研究の最後に、細胞増殖をPromega製CellTitreGloによって測定した。EC50(nM)を、以下に示し、50%細胞成長阻害濃度として決定した。成果を挙げる化合物の選択基準には、標的受容体の高い発現を伴って3nM未満のEC50で細胞系を死滅させるなどの高い有効性が含まれる。また、成果を挙げる候補は、標的受容体の低度の発現と共に対照細胞系(T-47D)の相対的に低度の死滅によって決定される通り、低毒性および良好な治療ウィンドウを有するはずである。ADC25(図6)は、細胞系H1993、HCC827、SNU-5、およびH292において良好な細胞死滅有効性を示すが、Hs746T、EBC-1およびU87において有効性を示さなかった。ADC25は、陰性対照細胞系T-47Dを死滅させなかったので、良好な治療ウィンドウを示した。ADC26(図4)は、H1993およびSNu-5において良好な細胞死滅活性を示す。しかし、その他の6種の細胞系において活性ではない。ADC27(図5)は、H1993(EC50=11pM)およびSNu-5(EC50=75pM)において優れた細胞死滅活性を示す。ADC27はまた、Hs746Tおいて良好な有効性を示す(EC50=0.4nM)。ADC29(図7)は、細胞系Hs746Tにおいて良好な細胞死滅有効性を示すが、EBC-1、U87、HCC827、H1993およびT-47において有効性を示さなかった。
Example 10
This example provides the results (nM) of the EC50 assay for the specified ADCs described herein, measured in vitro in specific cells. The antibody used targets the receptor tyrosine kinase on the cell surface. Eight cancer cell lines with varying levels of receptor expression were sown on 96-well plates, as indicated by the plus or minus marks in the table below. The ADC was serially diluted, added onto cells for treatment and left for 5 days. At the end of the study, cell proliferation was measured by Promega CellTitreGlo. EC50 (nM) is shown below and determined as a 50% cell growth inhibitory concentration. Successful compound selection criteria include high efficacy, such as killing cell lines with an EC50 of less than 3 nM with high expression of target receptors. Also, successful candidates should have low toxicity and a good treatment window, as determined by the relatively low death of the control cell line (T-47D) along with the low expression of the target receptor. be. ADC25 (FIG. 6) showed good cell killing efficacy in cell lines H1993, HCC827, SNU-5, and H292, but not in Hs746T, EBC-1 and U87. ADC25 did not kill the negative control cell line T-47D, thus showing a good treatment window. ADC26 (FIG. 4) shows good cell killing activity in H1993 and SNu-5. However, it is not active in the other 6 cell lines. ADC27 (FIG. 5) shows excellent cell killing activity in H1993 (EC50 = 11pM) and SNu-5 (EC50 = 75pM). ADC27 also shows good efficacy at Hs746T (EC50 = 0.4nM). ADC29 (FIG. 7) showed good cell killing efficacy in cell line Hs746T, but not in EBC-1, U87, HCC827, H1993 and T-47.
実施例11
この実施例は、ヌードマウスのH292、HCC827、およびH1975ヒト異種移植腫瘍成長モデルにおける、低分子22、23、25、または27とコンジュゲートしたADCの有効性に関する結果を提供する。HCC827、H292、H1975細胞系を、ATCCから得た。細胞を、10%FBS(Seradigm 1500-500)およびペニシリンストレプトマイシン(Corning 30-002-CI)を含むRPMI1640 1×(Corning 10-041-CV)培地中、37℃において5%二酸化炭素加湿環境で培養した。細胞を2週間培養し、4回継代した後、収集した。細胞を、0.25%トリプシン(Corning 25-050-CI)を用いて収集した。注射前に、HCC827細胞を1:1比のHBSS(ハンクス緩衝塩溶液;Ward製470180-784)およびマトリゲル(Corning 354234)混合物に混合し、0.2ml当たり700万個の細胞を、各マウスの右上側腹部に皮下注射した。H292細胞をHBSSに再懸濁させ、0.2ml当たり500万個の細胞を、各マウスの右上側腹部に皮下注射した。H1975細胞をHBSSに再懸濁させ、0.2ml当たり300万個の細胞を、各マウスの右上側腹部に皮下注射した。
Example 11
This example provides results regarding the efficacy of ADCs conjugated to
これらの研究を通して、5~7週齢の雌性Nu/Nuマウス(Charles River)を使用した。 Throughout these studies, female Nu / Nu mice (Charles River) 5-7 weeks old were used.
マウスを受け取ったら、制御環境の室内でケージ1つ当たり5匹のマウスを収容した。げっ歯類の固形飼料および水を自由に摂取させた。マウスを実験室条件に72時間順化させた後、投与を開始した。順化期間中、動物の健康状態をモニタリングした。各ケージを、群番号および研究番号によって識別し、マウスを、耳標によって個々に識別した。 Upon receipt of the mice, 5 mice were housed per cage in a controlled environment. The rodents were allowed to freely ingest solid feed and water. Mice were acclimatized to laboratory conditions for 72 hours before administration was initiated. The health of the animals was monitored during the acclimatization period. Each cage was identified by group number and study number, and mice were individually identified by ear tags.
研究設計および投与レジメンを、表3に示す。
腫瘍の幅および長さの測定を、デジタルノギスを使用して接種後5~7日目に開始し、その後、腫瘍体積が約100~250mm3に達するまで週2回測定することによって、腫瘍成長をモニタリングした。腫瘍体積を、式:体積(mm3)=[長さ(mm)×幅(mm)2]/2を使用して算出した。腫瘍を所望の体積に段階分けしたら、動物を無作為化し、非常に大きいまたは小さい腫瘍を有するマウスを間引いた。マウスを、研究設計に示される1群当たりの動物数で、各群に分けた。次に、マウスを、PBS、または22、23、25もしくは27とコンジュゲートした抗体のいずれかで、研究設計に示される用量として静脈内処置した(0.2ml/動物)。腫瘍成長をモニタリングし、対照群の平均腫瘍量が2000mm3を超えたら、各群のマウスを屠殺した。 Tumor growth by starting tumor width and length measurements using a digital caliper 5-7 days after inoculation and then measuring twice weekly until the tumor volume reaches approximately 100-250 mm 3 . Was monitored. Tumor volume was calculated using the formula: volume (mm 3 ) = [length (mm) x width (mm) 2 ] / 2. Once the tumors were staged to the desired volume, animals were randomized and mice with very large or small tumors were decimated. Mice were divided into groups according to the number of animals per group shown in the study design. Mice were then intravenously treated with either PBS or an antibody conjugated to 22, 23, 25 or 27 at the dose indicated in the study design (0.2 ml / animal). Tumor growth was monitored and when the average tumor volume in the control group exceeded 2000 mm 3 , mice in each group were sacrificed.
腫瘍体積を、実験期間を通して週2回測定して、TGI(腫瘍成長阻害%)を決定した。各マウスの体重を、電子天秤によって週2回測定した。群の平均および標準偏差を算出し、統計分析(ダネット多重比較試験を伴う一元配置分散分析(one-way ANOVA);GraphPad Prism 6.0)を行った。すべての処置群をPBS群と比較した。P<0.05を、統計的に有意とみなした。 Tumor volume was measured twice weekly throughout the experimental period to determine TGI (% tumor growth inhibition). The body weight of each mouse was measured twice a week by an electronic balance. Group means and standard deviations were calculated and statistical analysis (one-way ANOVA with Danette multiplex test; GraphPad Prism 6.0) was performed. All treatment groups were compared to the PBS group. P <0.05 was considered statistically significant.
3mg/kgのcMet/EGFR-22およびNimo-22処置の単回投与では、PBSで処置した対照群と比較して、H292腫瘍成長が著しく阻害された。cMet-22は、処置後最初の10日間で腫瘍成長を阻害したが、腫瘍は、10日間以降、再び成長した(図8および9)。この研究では、3mg/kgのcMet/EGFR-22およびcMet-22の単回投与によって、処置後3~6日に皮膚発疹が示され、6~14日目の間に乾燥した鱗状皮膚が示された。こうした皮膚の問題は、14日目以降、回復した。研究中、処置に関係する著しい体重減少は観測されなかった(図10)。cMet/EGFR-22で処置した群において、最初の週の間に体重減少があったが、体重減少は一過性であり、全体重の10%未満であった。また、動物は、体重が再び増え、PBSで処置した対照群と比較して全体的に健康であった。 A single dose of 3 mg / kg of cMet / EGFR-22 and Nimo-22 treatment significantly inhibited H292 tumor growth compared to a control group treated with PBS. cMet-22 inhibited tumor growth in the first 10 days after treatment, but the tumor grew again after 10 days (FIGS. 8 and 9). In this study, a single dose of 3 mg / kg cMet / EGFR-22 and cMet-22 showed a skin rash 3-6 days after treatment and dry scaly skin between 6-14 days. Was done. These skin problems recovered after the 14th day. No significant treatment-related weight loss was observed during the study (Fig. 10). In the cMet / EGFR-22 treated group, there was weight loss during the first week, but the weight loss was transient, less than 10% of total weight. The animals also gained weight again and were generally healthy compared to the control group treated with PBS.
3mg/kgのcMet/EGFR-23、cMet-23、またはNimo-23処置の単回投与では、PBSで処置した対照群と比較して、それぞれH292腫瘍成長が著しく阻害された(図11および12)。cMet-23、cMet/EGFR-23、およびNimo-23で処置した群(3mg/kg)において、体重減少は観測されなかった(図13)。 A single dose of 3 mg / kg of cMet / EGFR-23, cMet-23, or Nimo-23 treatment significantly inhibited H292 tumor growth, respectively, compared to PBS-treated controls (FIGS. 11 and 12). ). No weight loss was observed in the cMet-23, cMet / EGFR-23, and Nimo-23 treated groups (3 mg / kg) (FIG. 13).
3mg/kgまたは1mg/kgのcMet/EGFR-25の単回投与では、H1975異種移植において著しい腫瘍成長阻害はなかった(図14)。3mg/kgもしくは1mg/kgのcMet/EGFR-27の単回投与、または0.3mg/kgのcMet-27の単回投与では、HCC827異種移植において著しい腫瘍成長阻害はなかった(図15)。研究中、著しい体重減少は観測されなかった(図16)。
本発明の実施形態において、例えば以下の項目が提供される。
(項目1)
式Iの構造を有する抗体薬物コンジュゲート(ADC)
または薬学的に許容されるその塩
[式中、
Abは、モノクローナル抗体であり、
L
1
-L
2
は、
からなる群から選択されるリンカーであり、波線は、Abとの結合点を示し、
L
2
-Xは、
の構造を有し、R
4
は、水素、C
1~6
アルキル、または-(CH
2
CH
2
O)
m
-であり、mは、1~24の整数であり、波線は、Dとの結合点を示し、
L
2
は、単一アミノ酸、2~10個のアミノ酸長を有するペプチド、-(CH
2
)
p
-、-(CH
2
CH
2
O)
m
-、-C(O)NH-、-NHC(O)-、PAB(p-アミノベンジル)、Val-Cit-PAB、Val-Ala-PAB、Ala-Ala-Asn-PAB、-R
6
OC(O)NR
5
-、-R
8
-S-S-R
7
、またはそれらの組合せからなる群から選択されるリンカーであり、R
5
は、水素、C
1~6
アルキル、-(CH
2
)
p
-、-(CH
2
CH
2
O)
m
-、またはそれらの組合せからなる群から選択され、R
6
は、アミノ酸、10個までのアミノ酸からなるペプチド、C
1~6
アルキル、-(CH
2
)
p
-、-(CH
2
CH
2
O)
m
-、-C(O)NH-、-NHC(O)-、PAB、Val-Cit-PAB、Val-Ala-PAB、Ala-Ala-Asn-PAB、またはそれらの組合せからなる群から選択され、R
7
は、C
2~6
アルキレン、-(CH
2
CH
2
O)
m
-からなる群から選択され、R
8
は、アミノ酸、10個までのアミノ酸からなるペプチド、C
1~6
アルキル、C
1~6
アルキレン、置換C
1~6
アルキレン、-C(O)NH-、-C(O)-NH-CHR
9
-CR
10
R
11
-、-NHC(O)-CHR
9
-CR
10
R
11
-、-(CH
2
CH
2
O)
m
-、PAB、Val-Cit-PAB、Val-Ala-PAB、Ala-Ala-Asn-PAB、またはそれらの組合せからなる群から選択され、
R
9
は、水素、C
1~6
アルキル、C
1~6
アルキレン、-(CH
2
CH
2
O)
m
-、-C(O)NH-、-NHC(O)-、-C(O)NH-(CH
2
)p-SO
3
H、C(O)NH-(CH
2
)p-CO
2
H、-NHC(O)-(CH
2
)p-SO
3
H、-NHC(O)-(CH
2
)p-CO
2
H、またはそれらの組合せからなる群から選択され、
R
10
およびR
11
は、それぞれ独立に、水素、C
1~6
アルキル、またはそれらの組合せからなる群から選択され、
-R
6
OC(O)NR
5
-は、R
5
またはR
6
を介してL
1
と接続し、
-R
8
-S-S-R
7
-は、R
8
を介してL
1
と接続し、
Dは、アマトキシンから誘導された薬物部分の活性薬剤であり、アルファ-アマニチン、ベータ-アマニチン、ガンマ-アマニチン、およびイプシロン-アマニチンからなる群から選択され、
nは、1~10の整数であり、
mは、1~24の整数であり、
pは、1~6の整数である]。
(項目2)
Dが、式IIの構造
を有し、波線が、Xとの結合点を示し、
R
1
が、NH
2
またはOR
2
であり、R2が、H、またはC1~C10アルキルであり、R3が、HまたはOHである、項目1に記載のADC。
(項目3)
前記ADCが、
からなる群から選択される、項目1に記載のADC。
(項目4)
式
を有するADC。
(項目5)
式
を有するADC。
(項目6)
式
を有するADC。
(項目7)
式
を有するADC。
(項目8)
式
を有するADC。
(項目9)
式
を有するADC。
(項目10)
式
を有するADC。
A single dose of 3 mg / kg or 1 mg / kg of cMet / EGFR-25 did not significantly inhibit tumor growth in H1975 xenografts (FIG. 14). A single dose of 3 mg / kg or 1 mg / kg of cMet / EGFR-27 or a single dose of 0.3 mg / kg of cMet-27 did not significantly inhibit tumor growth in HCC827 xenografts (FIG. 15). No significant weight loss was observed during the study (Fig. 16).
In the embodiment of the present invention, for example, the following items are provided.
(Item 1)
Antibody drug conjugate (ADC) having the structure of formula I
Or its pharmaceutically acceptable salt
[During the ceremony,
Ab is a monoclonal antibody,
L 1 -L 2 is
It is a linker selected from the group consisting of, and the wavy line indicates the connection point with Ab.
L2 - X is
R 4 is hydrogen, C 1 to 6 alkyl, or-(CH 2 CH 2 O) m- , m is an integer of 1 to 24, and the wavy line is the bond with D. Show a point,
L 2 is a single amino acid, a peptide having a length of 2 to 10 amino acids,-(CH 2 ) p -,-(CH 2 CH 2 O) m- , -C (O) NH-, -NHC (O). )-, PAB (p-aminobenzyl), Val-Cit-PAB, Val-Ala-PAB, Ala-Ala-Asn-PAB, -R 6 OC (O) NR 5- , -R 8 -SS- A linker selected from the group consisting of R 7 or a combination thereof, where R 5 is hydrogen, C 1-6 alkyl,-(CH 2 ) p -,-(CH 2 CH 2 O) m- , or Selected from the group consisting of combinations thereof, R 6 is an amino acid, a peptide consisting of up to 10 amino acids, C 1 to 6 alkyl,-(CH 2 ) p -,-(CH 2 CH 2 O) m- , Selected from the group consisting of -C (O) NH-, -NHC (O)-, PAB, Val-Cit-PAB, Val-Ala-PAB, Ala-Ala-Asn-PAB, or a combination thereof, R 7 Is selected from the group consisting of C 2-6 alkylene,-(CH 2 CH 2 O) m-, and R 8 is an amino acid , a peptide consisting of up to 10 amino acids, C 1-6 alkyl, C 1-6 . Alkylene, substituted C 1-6 alkylene, -C (O) NH-, -C (O) -NH-CHR 9 - CR 10 R 11- , -NHC (O) -CHR 9 - CR 10 R 11 -,- (CH 2 CH 2 O) selected from the group consisting of m- , PAB, Val-Cit-PAB, Val-Ala-PAB, Ala-Ala-Asn-PAB, or a combination thereof.
R 9 is hydrogen, C 1 to 6 alkyl, C 1 to 6 alkylene,-(CH 2 CH 2 O) m- , -C (O) NH-, -NHC (O)-, -C (O) NH. -(CH 2 ) p-SO 3 H, C (O) NH- (CH 2 ) p-CO 2 H, -NHC (O)-(CH 2 ) p-SO 3 H, -NHC (O)-( CH 2 ) p-CO 2 H, or a combination thereof, selected from the group
R 10 and R 11 are each independently selected from the group consisting of hydrogen, C1-6 alkyl, or a combination thereof .
-R 6 OC (O) NR 5 -is connected to L 1 via R 5 or R 6 and
-R 8 -SS-R 7- is connected to L 1 via R 8 and
D is the active agent of the drug portion derived from amatoxin, selected from the group consisting of alpha-amanitin, beta-amanitin, gamma-amanitin, and epsilon-amanitin.
n is an integer from 1 to 10.
m is an integer from 1 to 24,
p is an integer from 1 to 6].
(Item 2)
D is the structure of formula II
The wavy line indicates the point of connection with X,
The ADC according to
(Item 3)
The ADC
The ADC according to
(Item 4)
formula
ADC with.
(Item 5)
formula
ADC with.
(Item 6)
formula
ADC with.
(Item 7)
formula
ADC with.
(Item 8)
formula
ADC with.
(Item 9)
formula
ADC with.
(Item 10)
formula
ADC with.
Claims (21)
[式中、
Abは、モノクローナル抗体であり、
L1-L2は、
L2-Xは、
L2は、(a)-R6OC(O)NR5-、および(b)-(CH2)p-、-(CH2CH2O)m-、-C(O)NH-、-NHC(O)-、またはそれらの2つ以上の組合せを含むリンカーであり、
R5は、水素、C1~6アルキル、-(CH2)p-、-(CH2CH2O)m-、または-(CH 2 ) p -および水素、-(CH 2 ) p -およびC 1-6 アルキル、-(CH 2 CH 2 O) m -および水素、-(CH 2 CH 2 O) m -およびC 1-6 アルキル、または-(CH 2 ) p -および-(CH 2 CH 2 O) m -の組合せであり、
ここで、R 5 が、-(CH 2 ) p -、-(CH 2 CH 2 O) m -、または-(CH 2 ) p -および-(CH 2 CH 2 O) m -の組合せである場合、R 5 は、L 1 、水素、またはC 1-6 アルキルと接続しており、
R6は、Val-Cit-PABまたはAla-Ala-Asn-PABであり、
ここで、-R6OC(O)NR5-は、R5またはR6を介してL1と接続し、
Dは、式(II):
ここで、R1は、NH2またはOR2であり、R2は、HまたはC1~10アルキルであり、そしてR3は、HまたはOHであり、そして
波線は、Xとの結合点を示し、
nは、1~10の整数であり、
mは、1~24の整数であり、
pは、1~6の整数である]。 Antibody drug conjugate (ADC) having the structure of formula (I)
Ab is a monoclonal antibody,
L 1 -L 2 is
L2 - X is
L 2 is (a) -R 6 OC (O) NR 5- , and (b)-(CH 2 ) p -,-(CH 2 CH 2 O) m- , -C (O) NH-,- NHC (O)-or a linker containing two or more combinations thereof.
R 5 is hydrogen, C 1-6 alkyl,-(CH 2 ) p -,-(CH 2 CH 2 O) m- , or-(CH 2 ) p- and hydrogen,-(CH 2 ) p -and C 1-6 alkyl,-(CH 2 CH 2 O) m- and hydrogen,-(CH 2 CH 2 O) m- and C 1-6 alkyl, or-(CH 2 ) p- and- (CH 2 CH ) 2 O) It is a combination of m-
Here, when R 5 is a combination of-(CH 2 ) p -,-(CH 2 CH 2 O) m- , or-(CH 2 ) p- and-(CH 2 CH 2 O) m- . , R 5 is connected to L 1 , hydrogen, or C 1-6 alkyl.
R 6 is Val-Cit-PAB or Ala-Ala-Asn-PAB.
Here, -R 6 OC (O) NR 5 --is connected to L 1 via R 5 or R 6 .
D is the formula (II):
Where R 1 is NH 2 or OR 2 , R 2 is H or C 1-10 alkyl, and R 3 is H or OH, and the wavy line is the point of connection with X. Show,
n is an integer from 1 to 10.
m is an integer from 1 to 24,
p is an integer from 1 to 6].
前記ADCが、
The ADC
ここで、R1が、NH2またはOHであり、そしてR3が、HまたはOHであり、
そして波線が、Xとの結合点を示す、
請求項1および9~19のいずれか1項に記載のADCまたは薬学的に許容されるその塩。 D is the formula (II):
Here, R 1 is NH 2 or OH, and R 3 is H or OH.
And the wavy line shows the point of connection with X,
The ADC or pharmaceutically acceptable salt thereof according to any one of claims 1 and 9-19.
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AU2017204139B2 (en) | 2016-06-17 | 2018-08-09 | Magenta Therapeutics, Inc. | Compositions and methods for the depletion of cells |
IL268058B2 (en) | 2017-01-20 | 2023-09-01 | Magenta Therapeutics Inc | Compositions and methods for the depletion of cd137plus cells |
WO2019197654A1 (en) * | 2018-04-13 | 2019-10-17 | Heidelberg Pharma Research Gmbh | Targeted amatoxin conjugate for the treatment of solid tumors |
CN113423430A (en) * | 2019-01-31 | 2021-09-21 | 杭州多禧生物科技有限公司 | Amanitoxin conjugates containing branched linkers |
CA3137373A1 (en) * | 2019-04-24 | 2020-10-29 | Heidelberg Pharma Research Gmbh | Amatoxin antibody-drug conjugates and uses thereof |
US20230115871A1 (en) * | 2019-06-24 | 2023-04-13 | Hangzhou Dac Biotech Co., Ltd | A conjugate of a cytotoxic agent to a cell binding molecule with branched linkers |
KR20220157425A (en) * | 2020-03-25 | 2022-11-29 | 지앙수 헨그루이 파마슈티컬스 컴퍼니 리미티드 | Methods for preparing antibody drug conjugates |
EP4301418A1 (en) | 2021-03-03 | 2024-01-10 | Sorrento Therapeutics, Inc. | Antibody-drug conjugates comprising an anti-bcma antibody |
CN113980909B (en) * | 2021-11-16 | 2022-06-14 | 江南大学 | Alpha-amanitin artificial antigen, monoclonal antibody, hybridoma cell strain and application |
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US20150218220A1 (en) * | 2012-09-12 | 2015-08-06 | Brian Alan MENDELSOHN | Amatoxin derivatives and cell-permeable conjugates thereof as inhibitors of rna polymerase |
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US9239324B2 (en) | 2013-12-06 | 2016-01-19 | Gang Chen | Antibody-binding protein-drug conjugate and methods of use |
MX2016007826A (en) * | 2013-12-16 | 2017-03-31 | Genentech Inc | Peptidomimetic compounds and antibody-drug conjugates thereof. |
WO2016004043A1 (en) * | 2014-06-30 | 2016-01-07 | Blend Therapeutics, Inc. | Targeted conjugates and particles and formulations thereof |
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